This invention is in the field of treatment of eye disease and more particularly in the area of treatments for glaucoma.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. The most common cause of glaucoma is restricted outflow of aqueous fluid from the anterior chamber of the eye through Schlemm's canal, the trabecular meshwork and the aqueous veins, shown in the diagram of the human eye in FIG. 1. Glaucoma, if untreated, can cause excavation and degeneration of the optic disc and nerve fiber bundle damage producing defects in the field of vision and eventually permanent blindness. Roughly two million Americans are afflicted, making glaucoma one of the leading causes of blindness in the United States.
Glaucoma may have a variety of causes, including hereditary predisposition, congential malformation, disease, injury or adverse drug reaction. For example, angle-closure glaucoma occurs because the outflow of the aqueous humor is mechanically prevented by contact of the iris with the trabecular drainage meshwork and peripheral cornea. Capsular glaucoma occurs in association with the widespread deposition of degenerative substance on the lens capsule, ocular blood vessels, iris and ciliary body. Corticosteroid-induced glaucoma is due to a hereditary predisposition to increased intraocular pressure after local installation of corticosteroid-containing eyedrops. Other types of glaucoma include hypersecretion glaucoma due to the excessive formation of aqueous humor; malignant glaucoma due to forward displacement of the iris and lens obliterating the anterior chamber; and open-angle glaucoma, in which the aqueous humor has free access to the trabecular meshwork.
Glaucoma is treated either surgically or with antiglaucomatous agents. Examples of antiglaucomatous agents include echothiophate iodide, pilocarpine, methazolamide, timolol, and epinephrine, dipivalyl epinephrine and other epinephrine salts. Echothiophate iodide is a long-acting cholinesterase inhibitor for topical use which enhances the effect of endogenously-liberated acetycholine in parasympathetically innervated structures of the eye to increase outflow of the aqueous humor to decrease intraocular pressure. Pilocarpine is a topically applied alkaloid which acts as a parasympathomimetic agent. Methazolamide is a potent inhibitor of the enzyme carbonic anahydrase which is taken orally and acts to lower intraocular pressure by inhibiting carbonic anhydrase in the various tissues of the eye. Timolol maleate is a general beta-adrenergic receptor-blocking agent which is effective in decreasing intraocular pressure. Epinephrine bitartrate, (-)-3,4,-Dihydroxy-alpha [(methylamino) methyl] benzyl alcohol (+) tartrate (1:1) salt, is an adrenergic agent which reduces intraocular pressure by reducing the rate of aqueous formation and increasing the outflow of aqueous humor from the eye. Apraclonidine hydrochloride (available as IPODINE, a trademark of Alcon Laboratories, Forth Worth, TX) is a relatively selective, alpha adrenergic agent which, when instilled into the eye, has the action of reducing intraocular pressure. A more detailed description is given in The Physicians Desk Reference (PDR) for Orthomology, 1989, pp 76-77.
Epinephrine is a very effective drug against glaucoma and deserves use as the initial medical treatment of mild cases as well as in addition to other medications when required for control of difficult cases. Clinical studies, reported in Ocular Pharmacology, at pages 275-290 by William H. Havener (The C. V. Mosby Co., St. Louis, 1983,) of a number of sympathomimetic compounds showed that a 1% to 2% solution of levo-epinephrine often helps to control glaucoma.
For example, topical application of a 2% solution of levo-epinephrine to 44 glaucomatous eyes caused an average drop in pressure of 13.5 mmHg, ranging from 3 to 38 mmHg. A marked pressure drop was obtained within 1 hour, and pressure continued to fall slightly for 4 hours. A slow rise followed, with a good effect lasting for 12 hours and a slight effect for as long as 24 hours. Eyes most likely to respond well to a 2% solution of levo-epinephrine were those with a coefficient of outflow better than 0.15, the pressures of which were maintained in the upper twenties with miotics. The pressure in most of these eyes could be dropped to the low twenties or below by instillation of a 2% solution of levo-epinephrine twice daily. Although in some instances glaucoma could be controlled by a 2% concentration of levo-epinephrine alone, the best results were obtained when this drug was used in combination with a miotic such as pilocarpine.
It is desirable to use as low a concentration of epinephrine as possible since epinephrine frequently causes side effects such as local allergy and systemic cardiovascular adrenergic responses and it may cause angle-closure glaucoma and aphakic maculopathy. A statistically significant pressure-lowering effect can be demonstrated with epinephrine concentrations as low as 0.5%. However, a substantially greater response occurs with a 1% to 2% solution. Dipivalyl epinephrine is a lipophilic epinephrine derivative and is converted to epinephrine in the ocular tissue. It is reported to have fewer side effects than epinephrine, (William H. Havener, Ocular Pharmacology at pages 287-289).
In general, drugs such as steroids are not used in the treatment of glaucoma. Rather, prolonged use of steroids such as dexamethasone sodium phosphate can result in elevated intraocular pressure, damage to the optic nerve, defects in visual acuity and fields of vision, posterior subcapsular cataract formation or secondary ocular infections. Further, viral, bacterial and fungal infections of the cornea may be exacerbated by the topical application of steroids to the eye.
Although the antiglaucomatous agents are generally effective in the treatment of glaucoma, they have both systemic and local side effects which may be serious in combination with other medical treatments such as anesthesia or the systemic use of other drugs. Beta blocker drugs such as timolol, and levobunolol cannot be used with people suffering from asthma or heart problems.
Systemic effects of epinephrine include increased blood pressure, faintness, headaches, and interactions with anesthesia. The side effects of topical epinephrine include burning, slow wound healing, pigment deposition and eyelash loss. Early commercial preparations of levo-epinephrine produced a very severe burning sensation, which was often sufficiently marked to incapacitate the patient for a minute or so and required preliminary use of a local anesthetic in some patients. Presently available preparations still cause tearing, burning and ocular discomfort. Mitosis and migration of corneal epithelial cells is inhibited by epinephrine and the time required for healing of corneal epithelial defects is doubled. Prolonged topical use of levo-epinephrine occasionally causes a local conjunctival allergy and localized conjunctival deposits of pigment. Corneal pigmentation caused by epinephrine is particularly likely to occur in eyes with a damaged epithelium and is enhanced by the use of old and discolored solutions of oxidized epinephrine. Topical epinephrine therapy can also cause plastic artificial eyes and contact lenses to turn black.
The side effects of topical epinephrine therapy are quite annoying. In one series of 50 patients, reported in Ocular Pharmacology by William H. Havener at pages 275-290, only 20% could continue epinephrine drops for a four-year period. Reactive hyperemia, irritation, and tearing affected two-thirds of the patients. Headaches affected 5 patients; cardiac palpitations, 4; blurred vision, 10; allergy, 6; and conjunctivial pigmentation, 12.
Adverse reactions reported in association with the use of the alpha adrenergic agonist IOPIDINE Ophthalmic Solution (apraclonidine hydrochloride) in laser surgery are upper lid elevation (1.3%), conjunctival blanching (0.4%) and mydriasis (0.4%). Other adverse events have been observed in investigational studies dosing IOPIDINE Ophthalmic Solution once or twice daily for up to 28 days in nonlaser studies, including, for example, the above mentioned events, ocular burning, discomfort, foreign body sensation, dryness, itching, hypotony, blurred or dimmed vision, allergic response, conjunctival microhemorrhage, in additional to other adverse events including, some in the gastrointestinal, cardiovascular, and central nervous systems. (PDR for Orthomology, 1989, pp. 76-77.)
It is therefore an object of the present invention to provide a method of treatment of glaucoma which is safe, effective, and has a minimum of side effects.
It is a further objective of the present invention to provide a method of treatment of glaucoma which utilizes a minimum of biologically-active compounds.
It is still a further objective of the present invention to provide a method for treatment of glaucoma which produces a decrease in ocular pressure which is of a reasonable duration.